This proposal will develop a new, small molecule drug to be advanced into human clinical trials in the chronic post-TBI patient, who still has chronic cognitive impairments months to years after the initial TBI. According to the Centers for Disease Control, approximately 3 million Americans suffer from post-TBI cognitive impairments. This includes people sustaining multiple concussions due to sports injury, Armed Forces personnel post- deployment with post-concussive syndrome, and persons sustaining accidental injury. This is an unmet medical need for which there is no adequate therapeutic agent. Our team proposes to develop a phosphodiesterase-4B (PDE4B) inhibitor as a therapeutic for post-TBI cognitive impairment. This will be a first-in-class drug with a novel, innovative mechanism of action against a therapeutic target that has not been explored previously in human clinical trials. Our preliminary data demonstrate that treatment of brain-injured rats with a PDE4B inhibitor beginning 3 months after injury improves multiple domains of learning and memory. PDE4B subtype-selective inhibitors avoid the well-known emetic side-effect of earlier PDE4 inhibitors that inhibit all subtypes of PDE4. Thus, PDE4B inhibitors are potentially breakthrough drugs for treating chronic cognitive deficits after TBI with improved tolerability. This Phase I STTR seeks to address limitations of the current PDE4B inhibitor (A-33) which has limited distribution to brain. Tetra has discovered a new series of PDE4B inhibitors with significantly improved brain distribution. Therefore, the goal of the project is to learn if an exemplar of the new family of PDE4B inhibitors (T-094) has benefit in the post-TBI model with adequate safety and tolerability. This proposal has the following three Aims. Aim 1 will evaluate the efficacy of T-094 in a rat TBI model. Multiple memory tasks and domains of memory will be evaluated. Go/No-Go criteria for success will be improvement in cognitive performance in comparison to TBI animals treated with vehicle. In Aim 2, T-094 will be evaluated for off-target activity against a panel of GPCR, ion channels, transporters and the cardiac hERG channel. Go/No-Go criteria for success will be acceptable safety margin based on anticipated brain exposure for efficacy. In Aim 3, T-094 will be assessed for tolerability in the ferret emesis model to determine the no observable effect level (NOEL) for emesis. Go/No-Go criteria will be a Therapeutic Index of >50 fold comparing plasma and brain exposure at the NOEL for emetic tolerability in ferret versus plasma and brain exposure that improves cognition in post-TBI rats. The Phase II project will transition to an SBIR for the evaluation of T-094 in additional TBI models, compare metabolite profiles in species to conduct toxicological assessments, assess pharmacokinetics in non-rodent species, and to complete dose-range finding toxicological studies in rat.